Isoxazole derivatives for use as plant growth regulators

ABSTRACT

The present invention relates to isoxazole compounds of formula (I) having plant growth regulating properties, to agricultural compositions comprising them, and to the use of said compounds for regulating plant growth.

The present invention relates to isoxazole compounds having plant growth regulating properties, to agricultural compositions comprising them, and to the use of said compounds for regulating plant growth.

Plant growth regulators (PGRs) are generally any substances or mixtures of substances intended to accelerate or retard the rate of growth or maturation, or otherwise alter the development of plants or their produce. PGRs affect growth and differentiation of plants, a process which is commonly and hereinafter referred to as “plant health”. There exists a need for further substances having PGR activity.

International patent application WO2006/031631 refers to a series of isoxazole derivatives having fungicidal properties.

It has surprisingly been found that the isoxazole compounds of the present invention exhibit plant growth regulating properties and are therefore suitable for use in agriculture for the improvement and control of plant health.

Accordingly, in a first aspect, the present invention provides for the use of a compound of the formula (I)

wherein:

R₁ is alkyl optionally substituted with hydroxy, phenyl or halophenyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, phenoxy, alkoxyalkynyl, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₂ is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₃ is H; alkyl; alkoxy; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkynyl, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or alkylsilyl; and

R₄ is H or acyl;

or a salt thereof; as a plant growth regulator.

Plant growth regulators can, for example, reduce plant height, stimulate seed germination, induce flowering, darken leaf coloring, change the rate of plant growth and modify the timing and efficiency of fruiting. In addition, PGRs may exhibit pronounced growth-regulating properties which can result in an increase in the yield of cultivated plants or harvested crops.

PGRs may also have a growth inhibiting action which is dependent on concentration. The growth of both monocots and dicots may be inhibited. Inhibition of the vegetative growth of many cultivated plants permits more plants to be sown in a crop area, so that a higher yield may be obtained per unit of area. Inhibition of the vegetative growth of monocot plants, e.g. cultivated plants such as cereals, is sometimes desirable and advantageous. Such a growth inhibition is of economic interest.

The use of PGRs for inhibiting the growth in height of cereals is also important, as shortening the stalks diminishes or completely eliminates the danger of lodging before harvesting. Additionally, PGRs are able to bring about a strengthening of the stalks in crops of cereals and this too counteracts lodging.

Furthermore, the present invention also provides compositions comprising the isoxazole derivatives of the present invention that improve plants, a process which is commonly and hereinafter referred to as “plant health”.

For example, advantageous properties that may be mentioned are improved crop characteristics including: emergence, crop yield, protein content, increased vigour, faster/delayed maturation, increased speed of seed emergence, improved nutrient utilization efficiency, improved nitrogen utilization efficiency, improved water use efficiency, improved oil content and/or quality, improved digestibility, faster/more even ripening, improved flavor, improved starch content, more developed root system (improved root growth), improved stress tolerance (e.g. against drought, heat, salt, light, UV, water, cold), reduced ethylene (reduced production and/or inhibition of reception), tillering increase, increase in plant height, bigger leaf blade, less dead basal leaves, stronger tillers, greener leaf color, pigment content, photosynthetic activity, less input needed (such as fertilizers or water), less seeds needed, more productive tillers, earlier flowering, early grain maturity, less plant verse (lodging), increased shoot growth, enhanced plant vigor, increased plant stand and early and better germination.

Advantageous properties obtained, especially from treated seeds, include, for example, improved germination and field establishment, better vigor and more homogeneous field establishment.

Advantageous properties obtained, especially from foliar and/or in-furrow application include, for example, improved plant growth and plant development, better growth, more tillers, greener leafes, largers leaves, more biomass, better roots, improved stress tolerance of the plants, more grain yield, more biomass harvested, improved quality of the harvest (content of fatty acids, metabolites, oil etc), more marketable products (e.g. improved size), improved process (e.g. longer shelf-life, better extraction of compounds), improved quality of seeds (for being seeded in the following seasons for seed production); or any other advantages familiar to a person skilled in the art.

It is therefore an object of the present invention to provide compositions and methods suitable for addressing the opportunities outlined above.

The present invention provides plant-protecting active ingredients that are isoxazole compounds of formula (I) according to the invention, in particular the individual isoxazole compounds described in the description as being preferred, and mixtures with increased efficacy and to a method of improving the health of plants by applying said compounds and mixtures to the plants or the locus thereof.

The action of the compounds of formula (I) is separate to any fungicidal action. The isoxazole compounds of formula (I) according to the invention, in particular the individual isoxazole compounds described in the above description as being preferred compounds exhibit plant health properties.

The present invention also concerns compositions comprising or consisting essentially of an active compound as described herein in combination with a suitable carrier (e.g., an agricultural carrier).

The foregoing and other objects and aspects of the present invention are explained in greater detail below.

“Alkyl” as used herein refers to a saturated hydrocarbon radical which may be straight-chain or branched-chain or cyclic (cycloalkyl) and contains from 1 to 24 carbon atoms. This definition applies both when the term is used alone and when it is used as part of a compound term, such as haloalkyl and similar terms. Preferred straight chain and branched alkyl groups may contain 1 to 8 carbon atoms, more preferably 1 to 4 carbons, even more preferably, 1 to 4 carbon atoms. Representative alkyl groups include, for example, methyl, ethyl, isopropyl, n-propyl, n-butyl, t-butyl, t-amyl, and 2,5-dimethylhexyl. Preferred cycloalkyl groups may contain 3 to 12 carbon atoms, more preferably 4 to 10 carbons, even more preferably, 5 to 8 carbon atoms and most preferably 5 or 6 carbon atoms. Preferred cycloalkyl groups include, for example, cyclobutyl, cyclopropyl, cyclopentyl and cyclohexyl.

“Alkenyl” as used herein, refers to a straight or branched chain hydrocarbon containing from 2 to 24 carbons, more preferably 2 to 8 carbons, yet more preferably, 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, and containing at least one carbon-carbon double bond. Representative alkenyl groups include, for example, ethenyl, 2-propenyl, 2-methyl-2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl and 3-decenyl.

“Alkynyl” as used herein, refers to a straight or branched chain hydrocarbon group containing from 2 to 24 carbons, more preferably 2 to 8 carbons, yet more preferably, 2 to 6 carbon atoms, even more preferably 2 to 4 carbon atoms, and containing at least one carbon-carbon triple bond. Representative alkynyl groups include, for example, acetylenyl, 1-propynyl, 2-propynyl, 3-butynyl, 2-pentynyl and 1-butynyl.

Representative alkoxy groups include, for example, methoxy, ethoxy and t-butoxy.

Representative alkylthio groups include, for example, methylthio, ethylthio, t-butylthio and hexylthio.

“Heterocyclyl”, as used herein refers to a saturated or partially unsaturated cyclic hydrocarbon containing from 3 to 10 ring-atoms up to 4 of which may be hetero-atoms such as nitrogen, oxygen and sulfur. Examples of heterocyclyl groups are oxiranyl, azetidinyl, tetrahydrofuranyl, thiolanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, sulfolanyl, dioxolanyl, dihydropyranyl, tetrahydropyranyl, piperidinyl, pyrazolinyl, pyrazolidinyl, dioxanyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, azepinyl, oxazepinyl, thiazepinyl, thiazolinyl and diazapanyl.

“Aryl” refers to an aromatic substituent which may be a single ring or multiple rings which are fused together, linked covalently or linked to a common group such as an ethylene or methylene moiety. The aromatic rings may each contain heteroatoms and hence aryl encompasses heteroaryl as used herein. Aryl moieties may be optionally substituted with 1 to 4 substituents independently selected from halogen, nitro, alkylcarboxyl, alkoxy and phenoxy. Representative examples of aryl include phenyl azulenyl, indanyl, indenyl, naphthyl, tetrahydronaphthyl, biphenyl, diphenylmethyl, 2,2-diphenyl-1-ethyl, thienyl, pyridyl and quinoxalyl. Most preferably, aryl is phenyl.

“Heteroaryl” means a cyclic, aromatic hydrocarbon containing 3 to 10 ring-atoms including 1 to 4 heteroatoms independently selected from nitrogen, oxygen and sulfur. Preferred heteroaryl groups are five and six membered rings and contain from one to three heteroatoms independently selected from nitrogen, oxygen and sulphur. Heteroaryl moieties may be optionally substituted with 1 to 4 substituents independently selected from halogen, nitro, alkylcarboxyl, alkoxy and phenoxy. Examples of heteroaryl groups include furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyranyl, pyridazinyl, tetrazolyl, triazinyl.

In addition, the term heteroaryl includes fused heteroaryl groups, for example benzimidazolyl, benzoxazolyl, imidazopyridinyl, benzoxazinyl, benzothiazinyl, oxazolopyridinyl, benzofuranyl, quinolinyl, quinazolinyl, quinoxalinyl, benzothiazolyl, phthalimido, benzofuranyl, benzodiazepinyl, indolyl, isoindolyl, isobenzofuranyl, chromenyl, xanthenyl, indolizinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, phthalazinyl, naphthyridinyl and benzo[b]thienyl.

Acyl includes any readily hydrolysable acyl groups, and comprises, for example, C(O)R⁵, C(O)OR⁵, C(O)NHR⁵ and C(O)NR⁵R⁶, wherein R⁵ and R⁶ are each independently selected from alkyl, alkenyl, akynyl, heterocyclyl, aryl and heteroaryl. Acyl groups may be optionally substituted with one or more, for example 1, 2, 3 or 4, halo or OR⁵ groups. Preferred acyl groups are acetyl, benzoyl and phenylacetyl.

“Halo” or “halogen” means fluoro, chloro, bromo and iodo and is preferably fluoro or chloro.

“Haloalkyl” includes monohaloalkyl, polyhaloalkyl and perhaloalkyl, for example, chloromethyl, 2-bromoethyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, chlorodifluoromethyl, trichloromethyl, trifluoromethyl, pentafluoroethyl and 2-chloro-3-fluoropentyl.

“Organic base” as used herein includes, for example, triethylamine, triisobutylamine, triiooctylamine, triisodecylamine, diethanolamine, triethanolamine, pyridine, morpholine, and mixtures thereof. A preferred category of organic base is organic amines.

“Inorganic base” as used herein includes, for example, sodium carbonate, sodium bicarbonate, potassium carbonate, and mixtures thereof.

“Inert solvent” as used herein includes any suitable inert solvent including, for example, tetrahydrofuran, N-methylpyrrolidone, dimethylformamide, toluene, dimethyl ether, methyl t-butyl ether and dioxane, methylene chloride, chloroform, 1,2-dichloroethane, and mixtures thereof.

“Protic solvent” as used herein may be any suitable protic solvent including, for example, methanol, ethanol, isopropanol, n-butanol, ethylene glycol, methyl Cellosolve, ethyl Cellosolve, cyclohexanol, glycerol, diethylene glycol, triethanolamine, polyethylene glycol, sec-butanol, n-propanol and tert-butanol.

“Optionally substituted” means substituted by one or more substituents, in particular, one, two, three or four substituents. In the case where groups may be selected from a number of alternative groups, the selected groups may be the same or different.

“Agriculturally acceptable salt” means a salt the cation of which is known and accepted in the art for the formation of salts for agricultural or horticultural use. Preferably the salts are water-soluble.

The compounds of formula (I) may exist in different geometric or optical isomeric forms or in different tautomeric forms. One or more centres of chirality may be present, in which case compounds of the formula (I) may be present as pure enantiomers, mixtures of enantiomers, pure diastereomers or mixtures of diastereomers. There may be double bonds present in the molecule, such as C═C or C═N bonds, in which case compounds of formula (I) may exist as single isomers of mixtures of isomers. Centres of tautomerisation may be present. This invention covers all such isomers and tautomers and mixtures thereof in all proportions as well as isotopic forms such as deuterated compounds.

Suitable salts of the compounds of formula (I), include acid addition salts such as those with an inorganic acid such as hydrochloric, hydrobromic, sulphuric, nitric or phosphoric acid, or an organic carboxylic acid such as oxalic, tartaric, lactic, butyric, toluic, hexanoic or phthalic acid, or a sulphonic acid such as methane, benzene or toluene sulphonic acid. Other examples of organic carboxylic acids include haloacids such as trifluoroacetic acid.

N-oxides are oxidised forms of tertiary amines or oxidised forms of nitrogen containing heteroaromatic compounds. They are described in many books for example in “Heterocyclic N-oxides” by Angelo Albini and Silvio Pietra, CRC Press, Boca Raton, Fla., 1991.

In another aspect, the present invention provides a method of regulating plant growth of crops of useful plants, which comprises applying to said plants, to one or more parts of said plants, or to the locus thereof or plant propagation material, a compound of formula (I) as defined herein.

The preferred embodiments of the invention as defined below apply equally to each aspect and preferred aspects thereof of the invention as defined herein.

In a preferred embodiment, R₁ is aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, phenoxy, alkoxyalkynyl, cyano, nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

Preferably, R₁ is aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, phenoxy, alkoxyalkynyl, cyano, or nitro; or heteroaryl optionally substituted with halogen.

More preferably, R₁ is phenyl optionally substituted with halogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkoxy, phenoxy, methoxypropargyl, cyano, or nitro; or furanyl, thienyl, pyridyl, or benzothienyl, each optionally substituted with halogen.

Most preferably, R₁ is 2-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 2,4-difluorophenyl, 3,5-difluorophenyl, 4-trifluoro-methylphenyl, 4-trifluoromethoxyphenyl or 2-thienyl.

In another preferred embodiment, R₁ is alkyl optionally substituted with hydroxy, phenyl or halophenyl; or arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

Preferably, R₁ is C₁-C₆-alkyl optionally substituted with hydroxy, phenyl or halophenyl; or arylalkyl optionally substituted with halogen or alkyl.

More preferably, R₁ is C₁-C₆-alkyl; or phenyl-C₁-C₆-alkyl optionally substituted with halogen or C₁-C₆-alkyl.

Most preferably, R₁ is n-pentyl, t-butyl, benzyl or 4-chlorobenzyl.

In a preferred embodiment, R₂ is heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro.

Preferably, R₂ is pyridyl, pyrimidinyl or isoquinolyl, each optionally substituted with halogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkoxy, cyano, or nitro.

More preferably, R₂ is 2-, 3- or 4-pyridyl or 5-pyrimidinyl, each optionally substituted with halogen, C₁-C₆-haloalkyl, C₁-C₆-alkoxy or C₁-C₆-alkylthio.

Most preferably, R₂ is 2-pyridyl, 3-pyridyl, or 5-pyrimidinyl, each optionally substituted with methyl, chloro, fluoro, methoxy, thiomethoxy or trifluoromethyl.

In a preferred embodiment, R₃ is alkyl; alkoxy; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen; aryloxyalkyl optionally substituted with halogen; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkynyl, cyano or nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or alkylsilyl;

Preferably, R₃ is alkyl; alkoxy; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkynyl, cyano or nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano or nitro; or alkylsilyl.

More preferably, R₃ is C₁-C₆-alkyl; C₁-C₆-alkoxy; phenyl optionally substituted with halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, methoxypropargyl, cyano or nitro; furanyl, thienyl or pyridyl, each optionally substituted with halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy; or C₁-C₆-alkylsilyl.

More preferably, R₃ is phenyl, 3-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 3,5-difluorophenyl, 4-methylphenyl, 2-thienyl, 5-chloro-2-thienyl, 5-methyl-2-thienyl, 3-thienyl, t-butyl or trimethylsilyl.

In a preferred embodiment, R₄ is H, acetyl, benzoyl and phenylacetyl. Most preferably, R₄ is H.

In one preferred aspect of the present invention:

R₁ is alkyl optionally substituted with hydroxy, phenyl or halophenyl; arylalkyl optionally substituted with halogen or alkyl; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, phenoxy, alkoxyalkynyl, cyano, or nitro; or heteroaryl optionally substituted with halogen;

R₂ is heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro;

R₃ is alkyl; alkoxy; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen; aryloxyalkyl optionally substituted with halogen; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkynyl, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or alkylsilyl; and

R₄ is H or acetyl.

In a more preferred aspect of the present invention;

R₁ is C₁-C₆-alkyl; phenyl-C₁-C₆-alkyl optionally substituted with halogen or C₁-C₆-alkyl; phenyl optionally substituted with halogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkoxy, phenoxy, methoxypropargyl, cyano, or nitro; or furanyl, thienyl, pyridyl, or benzothienyl, each optionally substituted with halogen;

R₂ is pyridyl or pyrimidinyl, each optionally substituted with halogen, C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, C₁-C₆-haloalkoxy, cyano, or nitro;

R₃ is C₁-C₆-alkyl; C₁-C₆-alkoxy; phenyl optionally substituted with halogen, C₁-C₆-alkyl, C₁-C₆-haloalkyl, C₁-C₆-alkoxy, C₁-C₆-alkylthio, methoxypropargyl, cyano or nitro; furanyl, thienyl or pyridyl, each optionally substituted with halogen, C₁-C₆-alkyl or C₁-C₆-alkoxy; or C₁-C₆-alkylsilyl; and

R₄ is H.

Preferred compounds of formula (I) for use according to the methods of the present invention are selected from:

3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 144);

3-(4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 145);

3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole (compound 146);

3-(2,4-chlorophenyl)-5-(2-chlorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 147);

3-(2-fluoro-4-chlorophenyl)-5-(2-chlorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 148);

3-(4-chlorophenyl)-5-(2-methoxypyridine)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 149);

3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 150);

3-(4-chlorophenyl)-5-(2,4-fluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 151);

3-(2,4-fluoro-4-chlorophenyl)-5-(2-chloro-4-fluorophenyl)-4-[(3pyridyl)hydroxymethyl]-isoxazole (compound 152); and

(R)-3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole (compound 153);

and salts thereof.

In a further aspect, the present invention provides a method of regulating plant growth of crops of useful plants, which comprises applying to said plants, to one or more parts of said plants, or to the locus thereof or plant propagation material, a compound of formula (I) as defined herein, wherein said method comprises one or more applications of one or more compounds as defined herein alone or in conjunction with one or more customary plant protection formulating auxiliaries.

In a further aspect, the present invention provides a method of regulating plant growth of crops of useful plants, which comprises applying to said plants, to one or more parts of said plants, or to the locus thereof or plant propagation material, a compound of formula (I) as defined herein, wherein two or more applications are carried out in sequence, and wherein the two or more applications have the same or different concentration or combinations of compounds as defined herein or both.

In a preferred embodiment of the invention, the crops of useful plants are selected from cereals, rice, beets, leguminous plants, oil plants, cucumber plants, fibre plants, vegetables, plantation crops, ornamentals, vines, bushberries, caneberries, cranberries, peppermint, rhubarb, spearmint, sugar cane and turf grasses.

In a preferred embodiment of the invention, the plant growth regulating effect is an inhibition or a retardation of the plant growth.

In a further aspect, the present invention provides an agricultural composition comprising one or more compounds of formula (I) as defined herein and one or more customary plant protection auxiliaries.

Furthermore, one of the enantiomers of the compounds of formula (I) have been found to be significantly more active than the other enantiomer.

In a further aspect, the present invention is directed to the (R)-enantiomers of the compounds of formula (I), designated (R)-(I), wherein R₁, R₂, R₃ and R₄ are as defined herein; and salts thereof.

Preferred compounds of formula (R)-(I) include the (R)-enantiomers of compounds 1 to 153 of Table 1 and 154 to 195 of Table 2 herein.

The present invention provides the compound of formula (R)-(I) as a single enantiomer having an enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.

In a further aspect, the present invention is directed to the (S)-enantiomers of the compounds of formula (I), designated (S)-(I), wherein R₁, R₂, R₃ and R₄ are as defined herein; and salts thereof.

The present invention provides the compound of formula (S)-(I) as a single enantiomer having an enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.

Preferred compounds of formula (S)-(I) include the (S)-enantiomers of compounds 1 to 153 of Table 1 and 154 to 195 of Table 2 herein.

In another aspect, the present invention also relates to an agricultural composition comprising a compound of formula (R)-(I) a defined herein, or an agrochemically acceptable salt thereof, and an agrochemically acceptable diluent or carrier.

In a further aspect, the present invention also relates to an agricultural composition comprising a compound of formula (S)-(I) a defined herein, or an agrochemically acceptable salt thereof, and an agrochemically acceptable diluent or carrier.

In a another aspect, the present invention is directed to novel compounds of formula (I) selected from:

3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 144);

3-(4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 145);

3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole (compound 146);

3-(2,4-chlorophenyl)-5-(2-chlorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 147);

3-(2-fluoro-4-chlorophenyl)-5-(2-chlorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 148);

3-(4-chlorophenyl)-5-(2-methoxypyridine)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 149);

3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 150);

3-(4-chlorophenyl)-5-(2,4-fluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole (compound 151);

3-(2,4-fluoro-4-chlorophenyl)-5-(2-chloro-4-fluorophenyl)-4-[(3pyridyl)hydroxymethyl]-isoxazole (compound 152); and

(R)-3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole (compound 153);

and salts thereof.

“Plant propagation material” means the generative parts of a plant including seeds of all kinds (fruit, tubers, bulbs, grains etc), roots, rhizomes, cuttings, cut shoots and the like. Plant propagation material may also include plants and young plants which are to be transplanted after germination or after emergence from the soil.

“Locus” means the fields on which the plants to be treated are growing, or where the seeds of cultivated plants are sown, or the place where the seed will be placed into the soil.

The crops of useful plants to be protected typically comprise, for example, the following species of plants: cereals (wheat, barley, rye, oats, maize (including field corn, pop corn and sweet corn), rice, sorghum and related crops); beet (sugar beet and fodder beet); leguminous plants (beans, lentils, peas, soybeans); oil plants (rape, mustard, sunflowers); cucumber plants (marrows, cucumbers, melons); fibre plants (cotton, flax, hemp, jute); vegetables (spinach, lettuce, asparagus, cabbages, carrots, eggplants, onions, pepper, tomatoes, potatoes, paprika, okra); plantation crops (bananas, fruit trees, rubber trees, tree nurseries), ornamentals (flowers, shrubs, broad-leaved trees and evergreens, such as conifers); as well as other plants such as vines, bushberries (such as blueberries), caneberries, cranberries, peppermint, rhubarb, spearmint, sugar cane and turf grasses including, for example, cool-season turf grasses (for example, bluegrasses (Poa L.), such as Kentucky bluegrass (Poa pratensis L.), rough bluegrass (Poa trivialis L.), Canada bluegrass (Poa compressa L.) and annual bluegrass (Poa annua L.); bentgrasses (Agrostis L.), such as creeping bentgrass (Agrostis palustris Huds.), colonial bentgrass (Agrostis tenius Sibth.), velvet bentgrass (Agrostis canina L.) and redtop (Agrostis alba L.); fescues (Festuca L.), such as tall fescue (Festuca arundinacea Schreb.), meadow fescue (Festuca elatior L.) and fine fescues such as creeping red fescue (Festuca rubra L.), chewings fescue (Festuca rubra var. commutate Gaud.), sheep fescue (Festuca ovina L.) and hard fescue (Festuca longifolia); and ryegrasses (Lolium L.), such as perennial ryegrass (Lolium perenne L.) and annual (Italian) ryegrass (Lolium multiflorum Lam.)) and warm-season turf grasses (for example, Bermudagrasses (Cynodon L. C. Rich), including hybrid and common Bermudagrass; Zoysiagrasses (Zoysia Willd.), St. Augustinegrass (Stenotaphrum secundatum (Walt.) Kuntze); and centipedegrass (Eremochloa ophiuroides (Munro.) Hack.)).

The term “useful plants” also includes useful plants that have been rendered tolerant to herbicides like bromoxynil or classes of herbicides (such as HPPD inhibitors, ALS inhibitors; for example primisulfuron, prosulfuron and trifloxysulfuron, EPSPS (5-enol-pyrovyl-shikimate-3-phosphate-synthase) inhibitors, GS (glutamine synthetase) inhibitors or PPO (protoporphyrinogen-oxidase) inhibitors) as a result of conventional methods of breeding or genetic engineering. An example of a crop that has been rendered tolerant to imidazolinones (e.g. imazamox) by conventional methods of breeding (mutagenesis) is Clearfield® summer rape (Canola). Examples of crops that have been rendered tolerant to herbicides or classes of herbicides by genetic engineering methods include glyphosate- and glufosinate-resistant maize varieties commercially available under the trade names RoundupReady®, Herculex I® and LibertyLink®.

The term “useful plants” also includes useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising one or more selectively acting toxins, such as are known from toxin-producing bacteria, especially those of the genus Bacillus.

The term “useful plants” also includes useful plants which have been so transformed by the use of recombinant DNA techniques that they are capable of synthesising antipathogenic substances having a selective action, such as the so-called “pathogenesis-related proteins” (PRPs, see e.g. European patent application EP 0,392,225). Examples of such antipathogenic substances and transgenic plants capable of synthesising such antipathogenic substances are known, for example, from European patent applications EP 0,392,225 and EP 0,353,191, and International patent application WO 95/33818. The methods of producing such transgenic plants are generally known to the person skilled in the art and are described, for example, in the publications mentioned above.

The agrochemical compositions of the present invention will usually contain from 0.1 to 99% by weight, preferably from 0.1 to 95% by weight, of the compound of formula (I), 99.9 to 1% by weight, preferably 99.8 to 5% by weight, of a solid or liquid adjuvant, and from 0 to 25% by weight, preferably from 0.1 to 25% by weight, of a surfactant.

Suitably, the agrochemical compositions of the present invention are applied prior to disease development. Rates and frequency of use of the formulations are those conventionally used in the art and factors such as the developmental stage of the plant and on the location, timing and application method. Advantageous rates of application are normally from 5 g to 2 kg of active ingredient (a.i.) per hectare (ha), preferably from 10 g to 1 kg a.i./ha, most preferably from 20 g to 600 g a.i./ha. When used as seed drenching agent, convenient rates of application are from 10 mg to 1 g of active substance per kg of seeds.

In practice, as indicated above, the agrochemical compositions comprising a compound of formula (I) are applied as a formulation containing the various adjuvants and carriers known to or used in the industry. They may therefore be formulated as granules, wettable or soluble powders, emulsifiable concentrates, coatable pastes, dusts, flowables, solutions, suspensions or emulsions, or as controlled release forms such as microcapsules. These formulations are described in more detail below and may contain from 0.5% to 95% or more by weight of the active ingredient. The optimum amount will depend on formulation, application equipment and nature of the plant to be treated.

Suspension concentrates are aqueous formulations in which finely divided solid particles of the active compound are suspended. Such formulations include anti-settling agents and dispersing agents and may further include a wetting agent to enhance activity as well an anti-foam and a crystal growth inhibitor. In use, these concentrates are diluted in water and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.

Wettable powders are in the form of finely divided particles which disperse readily in water or other liquid carriers. The particles contain the active ingredient retained in a solid matrix. Typical solid matrices include fuller's earth, kaolin clays, silicas and other readily wet organic or inorganic solids. Wettable powders normally contain from 5% to 95% of the active ingredient plus a small amount of wetting, dispersing or emulsifying agent.

Emulsifiable concentrates are homogeneous liquid compositions dispersible in water or other liquid and may consist entirely of the active compound with a liquid or solid emulsifying agent, or may also contain a liquid carrier, such as xylene, heavy aromatic naphthas, isophorone and other non-volatile organic solvents. In use, these concentrates are dispersed in water or other liquid and normally applied as a spray to the area to be treated. The amount of active ingredient may range from 0.5% to 95% of the concentrate.

Granular formulations include both extrudates and relatively coarse particles and are usually applied without dilution to the area in which treatment is required. Typical carriers for granular formulations include sand, fuller's earth, attapulgite clay, bentonite clays, montmorillonite clay, vermiculite, perlite, calcium carbonate, brick, pumice, pyrophyllite, kaolin, dolomite, plaster, wood flour, ground corn cobs, ground peanut hulls, sugars, sodium chloride, sodium sulphate, sodium silicate, sodium borate, magnesia, mica, iron oxide, zinc oxide, titanium oxide, antimony oxide, cryolite, gypsum, diatomaceous earth, calcium sulphate and other organic or inorganic materials which absorb or which can be coated with the active compound. Granular formulations normally contain 5% to 25% of active ingredients which may include surface-active agents such as heavy aromatic naphthas, kerosene and other petroleum fractions, or vegetable oils; and/or stickers such as dextrins, glue or synthetic resins.

Dusts are free-flowing admixtures of the active ingredient with finely divided solids such as talc, clays, flours and other organic and inorganic solids which act as dispersants and carriers.

Microcapsules are typically droplets or granules of the active ingredient enclosed in an inert porous shell which allows escape of the enclosed material to the surroundings at controlled rates. Encapsulated droplets are typically 1 to 50 microns in diameter. The enclosed liquid typically constitutes 50 to 95% of the weight of the capsule and may include solvent in addition to the active compound. Encapsulated granules are generally porous granules with porous membranes sealing the granule pore openings, retaining the active species in liquid form inside the granule pores. Granules typically range from 1 millimetre to 1 centimetre and preferably 1 to 2 millimetres in diameter. Granules are formed by extrusion, agglomeration or prilling, or are naturally occurring. Examples of such materials are vermiculite, sintered clay, kaolin, attapulgite clay, sawdust and granular carbon. Shell or membrane materials include natural and synthetic rubbers, cellulosic materials, styrene-butadiene copolymers, polyacrylonitriles, polyacrylates, polyesters, polyamides, polyureas, polyurethanes and starch xanthates.

Other useful formulations for agrochemical applications include simple solutions of the active ingredient in a solvent in which it is completely soluble at the desired concentration, such as acetone, alkylated naphthalenes, xylene and other organic solvents. Pressurised sprayers, wherein the active ingredient is dispersed in finely-divided form as a result of vaporisation of a low boiling dispersant solvent carrier, may also be used.

Suitable agricultural adjuvants and carriers that are useful in formulating the compositions of the invention in the formulation types described above are well known to those skilled in the art.

Liquid carriers that can be employed include, for example, water, toluene, xylene, petroleum naphtha, crop oil, acetone, methyl ethyl ketone, cyclohexanone, acetic anhydride, acetonitrile, acetophenone, amyl acetate, 2-butanone, chlorobenzene, cyclohexane, cyclohexanol, alkyl acetates, diacetonalcohol, 1,2-dichloropropane, diethanolamine, p-diethylbenzene, diethylene glycol, diethylene glycol abietate, diethylene glycol butyl ether, diethylene glycol ethyl ether, diethylene glycol methyl ether, N,N-dimethyl formamide, dimethyl sulfoxide, 1,4-dioxane, dipropylene glycol, dipropylene glycol methyl ether, dipropylene glycol dibenzoate, diproxitol, alkyl pyrrolidinone, ethyl acetate, 2-ethyl hexanol, ethylene carbonate, 1,1,1-trichloroethane, 2-heptanone, alpha pinene, d-limonene, ethylene glycol, ethylene glycol butyl ether, ethylene glycol methyl ether, gamma-butyrolactone, glycerol, glycerol diacetate, glycerol monoacetate, glycerol triacetate, hexadecane, hexylene glycol, isoamyl acetate, isobornyl acetate, isooctane, isophorone, isopropyl benzene, isopropyl myristate, lactic acid, laurylamine, mesityl oxide, methoxy-propanol, methyl isoamyl ketone, methyl isobutyl ketone, methyl laurate, methyl octanoate, methyl oleate, methylene chloride, m-xylene, n-hexane, n-octylamine, octadecanoic acid, octyl amine acetate, oleic acid, oleylamine, o-xylene, phenol, polyethylene glycol (PEG400), propionic acid, propylene glycol, propylene glycol monomethyl ether, p-xylene, toluene, triethyl phosphate, triethylene glycol, xylene sulfonic acid, paraffin, mineral oil, trichloroethylene, perchloroethylene, ethyl acetate, amyl acetate, butyl acetate, methanol, ethanol, isopropanol, and higher molecular weight alcohols such as amyl alcohol, tetrahydrofurfuryl alcohol, hexanol, octanol, etc., ethylene glycol, propylene glycol, glycerine and N-methyl-2-pyrrolidinone. Water is generally the carrier of choice for the dilution of concentrates.

Suitable solid carriers include, for example, talc, titanium dioxide, pyrophyllite clay, silica, attapulgite clay, kieselguhr, chalk, diatomaxeous earth, lime, calcium carbonate, bentonite clay, fuller's earth, cotton seed hulls, wheat flour, soybean flour, pumice, wood flour, walnut shell flour and lignin.

A broad range of surface-active agents are advantageously employed in both said liquid and solid compositions, especially those designed to be diluted with carrier before application. These agents, when used, normally comprise from 0.1% to 15% by weight of the formulation. They can be anionic, cationic, non-ionic or polymeric in character and can be employed as emulsifying agents, wetting agents, suspending agents or for other purposes. Typical surface active agents include salts of alkyl sulfates, such as diethanolammonium lauryl sulphate; alkylarylsulfonate salts, such as calcium dodecylbenzenesulfonate; alkylphenol-alkylene oxide addition products, such as nonylphenol-C.sub. 18 ethoxylate; alcohol-alkylene oxide addition products, such as tridecyl alcohol-C.sub. 16 ethoxylate; soaps, such as sodium stearate; alkylnaphthalenesulfonate salts, such as sodium dibutylnaphthalenesulfonate; dialkyl esters of sulfosuccinate salts, such as sodium di(2-ethylhexyl)sulfosuccinate; sorbitol esters, such as sorbitol oleate; quaternary amines, such as lauryl trimethylammonium chloride; polyethylene glycol esters of fatty acids, such as polyethylene glycol stearate; block copolymers of ethylene oxide and propylene oxide; and salts of mono and dialkyl phosphate esters.

Other adjuvants commonly utilized in agricultural compositions include crystallisation inhibitors, viscosity modifiers, suspending agents, spray droplet modifiers, pigments, antioxidants, foaming agents, anti-foaming agents, light-blocking agents, compatibilizing agents, antifoam agents, sequestering agents, neutralising agents and buffers, corrosion inhibitors, dyes, odorants, spreading agents, penetration aids, micronutrients, emollients, lubricants and sticking agents.

In addition, further, other biocidally active ingredients or compositions may be combined with the compound of formula (I) and used in the methods of the invention and applied simultaneously or sequentially with the compound of formula (I). When applied simultaneously, these further active ingredients may be formulated together with the compound of formula (I) or mixed in, for example, the spray tank. These further biocidally active ingredients may be fungicides, herbicides, insecticides, bactericides, acaricides, nematicides and/or plant growth regulators.

Accordingly, in one aspect, the present invention provides a composition comprising a compound of formula (I), which is selected from compounds 143 to 153 of Table 1 and 154 to 195 of Table 2, and (i) a fungicide, (ii) a herbicide, (iii) an insecticide, (iv) a bactericide, (v) an acaricide, (vi) a nematicide and/or (vii) a plant growth regulator.

Additionally, the present invention provides for the use of a composition in the methods of the present invention, said composition comprising a compound of formula (I), which is selected from compounds 143 to 153 of Table 1 and 154 to 195 of Table 2, and (i) a fungicide, (ii) a herbicide, (iii) an insecticide, (iv) a bactericide, (v) an acaricide, (vi) a nematicide and/or (vii) a plant growth regulator.

In a further aspect, the present invention provides a composition comprising a compound of formula (I), which is the (R)-enantiomer of formula (R)-(I) and (i) a fungicide, (ii) a herbicide, (iii) an insecticide, (iv) a bactericide, (v) an acaricide, (vi) a nematicide and/or (vii) a plant growth regulator.

Additionally, the present invention provides for the use of a composition in the methods of the present invention, said composition comprising a compound of formula (I), which is the (R)-enantiomer of formula (R)-(I), and (i) a fungicide, (ii) a herbicide, (iii) an insecticide, (iv) a bactericide, (v) an acaricide, (vi) a nematicide and/or (vii) a plant growth regulator.

In a further aspect, the present invention provides a composition comprising a compound of formula (I), which is the (S)-enantiomer of formula (S)-(I) and (i) a fungicide, (ii) a herbicide, (iii) an insecticide, (iv) a bactericide, (v) an acaricide, (vi) a nematicide and/or (vii) a plant growth regulator.

Additionally, the present invention provides for the use of a composition in the methods of the present invention, said composition comprising a compound of formula (I), which is the (S)-enantiomer of formula (S)-(I), and (i) a fungicide, (ii) a herbicide, (iii) an insecticide, (iv) a bactericide, (v) an acaricide, (vi) a nematicide and/or (vii) a plant growth regulator.

In addition, the compounds of the invention may also be applied with one or more systemically acquired resistance inducers (“SAR” inducer). SAR inducers are known and described in, for example, U.S. Pat. No. 6,919,298 and include, for example, salicylates and the commercial SAR inducer acibenzolar-S-methyl.

In particular, compositions encompassed by the present invention include, for example, compositions comprising a compound of formula (I) and acibenzolar (CGA245704), a compound of formula (I) and ancymidol, a compound of formula (I) and alanycarb, a compound of formula (I) and aldimorph, a compound of formula (I) and amisulbrom, a compound of formula (I) and anilazine, a compound of formula (I) and azaconazole, a compound of formula (I) and azoxystrobin, a compound of formula (I) and benalaxyl, a compound of formula (I) and benthiavalicarb, a compound of formula (I) and benomyl, a compound of formula (I) and biloxazol, a compound of formula (I) and bitertanol, a compound of formula (I) and bixafen, a compound of formula (I) and blasticidin S, a compound of formula (I) and boscalid, a compound of formula (I) and bromuconazole, a compound of formula (I) and bupirimate, a compound of formula (I) and captafol, a compound of formula (I) and captan, a compound of formula (I) and carbendazim, a compound of formula (I) and carbendazim, a compound of formula (I) and chlorhydrate, a compound of formula (I) and carboxin, a compound of formula (I) and carpropamid, a compound of formula (I) and carvone, a compound of formula (I) and CGA41396, a compound of formula (I) and CGA41397, a compound of formula (I) and chinomethionate, a compound of formula (I) and chloroneb, a compound of formula (I) and chlorothalonil, a compound of formula (I) and chlorozolinate, a compound of formula (I) and clozylacon, a compound of formula (I) and copper containing compounds such as copper oxychloride, copper oxyquinolate, copper sulphate, copper tallate and Bordeaux mixture, a compound of formula (I) and cyflufenamid, a compound of formula (I) and cymoxanil, a compound of formula (I) and cyproconazole, a compound of formula (I) and cyprodinil, a compound of formula (I) and debacarb, a compound of formula (I) and di-2-pyridyl disulphide 1,1′-dioxide, a compound of formula (I) and dichlofluanid, a compound of formula (I) and diclomezine, a compound of formula (I) and dichlozoline, a compound of formula (I) and dichlone, a compound of formula (I) and dicloran, a compound of formula (I) and diclocymet, a compound of formula (I) and diethofencarb, a compound of formula (I) and difenoconazole, a compound of formula (I) and difenzoquat, a compound of formula (I) and diflumetorim, a compound of formula (I) and O,O-di-iso-propyl-S-benzyl thiophosphate, a compound of formula (I) and dimefluazole, a compound of formula (I) and dimetconazole, a compound of formula (I) and dimethomorph, a compound of formula (I) and dimethirimol, a compound of formula (I) and dimoxystrobin, a compound of formula (I) and diniconazole, a compound of formula (I) and dinocap, a compound of formula (I) and dithianon, a compound of formula (I) and dodecyl dimethyl ammonium chloride, a compound of formula (I) and dodemorph, a compound of formula (I) and dodine, a compound of formula (I) and doguadine, a compound of formula (I) and edifenphos, a compound of formula (I) and enestrobin, a compound of formula (I) and epoxiconazole, a compound of formula (I) and ethaboxam, a compound of formula (I) and ethirimol, a compound of formula (I) and etridiazole, a compound of formula (I) and famoxadone, a compound of formula (I) and fenamidone (RPA407213), a compound of formula (I) and fenarimol, a compound of formula (I) and fenbuconazole, a compound of formula (I) and fenfuram, a compound of formula (I) and fenhexamid (KBR2738), a compound of formula (I) and fenoxanil, a compound of formula (I) and fenpiclonil, a compound of formula (I) and fenpropidin, a compound of formula (I) and fenpropimorph, a compound of formula (I) and fentin acetate, a compound of formula (I) and fentin hydroxide, a compound of formula (I) and ferbam, a compound of formula (I) and ferimzone, a compound of formula (I) and fluazinam, a compound of formula (I) and fluopicolide, a compound of formula (I) and fludioxonil, a compound of formula (I) and fluoxastrobin, a compound of formula (I) and flumetover, a compound of formula (I) and SYP-LI90 (flumorph), a compound of formula (I) and fluopyram, a compound of formula (I) and fluoroimide, a compound of formula (I) and fluquinconazole, a compound of formula (I) and flusilazole, a compound of formula (I) and flusulfamide, a compound of formula (I) and flutolanil, a compound of formula (I) and flutriafol, a compound of formula (I) and folpet, a compound of formula (I) and fosetyl-aluminium, a compound of formula (I) and fuberidazole, a compound of formula (I) and furalaxyl, a compound of formula (I) and furametpyr, a compound of formula (I) and guazatine, a compound of formula (I) and hexaconazole, a compound of formula (I) and hydroxyisoxazole, a compound of formula (I) and hymexazole, a compound of formula (I) and IKF-916 (cyazofamid), a compound of formula (I) and imazalil, a compound of formula (I) and imibenconazole, a compound of formula (I) and iminoctadine, a compound of formula (I) and iminoctadine triacetate, a compound of formula (I) and ipconazole, a compound of formula (I) and iprobenfos, a compound of formula (I) and iprodione, a compound of formula (I) and iprovalicarb (SZX0722), a compound of formula (I) and isopropanyl butyl carbamate, a compound of formula (I) and isoprothiolane, a compound of formula (I) and kasugamycin, a compound of formula (I) and kresoxim-methyl, a compound of formula (I) and LY186054, a compound of formula (I) and LY211795, a compound of formula (I) and LY248908, a compound of formula (I) and maneb, a compound of formula (I) and mancopper, a compound of formula (I) and mancozeb, a compound of formula (I) and mandipropamid, a compound of formula (I) and mefenoxam, a compound of formula (I) and mepanipyrim, a compound of formula (I) and mepronil, a compound of formula (I) and metalaxyl, a compound of formula (I) and metconazole, a compound of formula (I) and methasulfocarb, a compound of formula (I) and metiram, a compound of formula (I) and metiram-zinc, a compound of formula (I) and metominostrobin, a compound of formula (I) and metrafenone, a compound of formula (I) and myclobutanil, a compound of formula (I) and myclozoline, a compound of formula (I) and neoasozin, a compound of formula (I) and nickel dimethyldithiocarbamate, a compound of formula (I) and nitrothal-isopropyl, a compound of formula (I) and nuarimol, a compound of formula (I) and ofurace, a compound of formula (I) and organomercury compounds, a compound of formula (I) and orysastrobin, a compound of formula (I) and oxadixyl, a compound of formula (I) and oxasulfuron, a compound of formula (I) and oxine-copper, a compound of formula (I) and oxolinic acid, a compound of formula (I) and oxpoconazole, a compound of formula (I) and oxycarboxin, a compound of formula (I) and pefurazoate, a compound of formula (I) and penconazole, a compound of formula (I) and pencycuron, a compound of formula (I) and penthiopyrad, a compound of formula (I) and phenazin oxide, a compound of formula (I) and phosdiphen, a compound of formula (I) and phosphorus acids, a compound of formula (I) and phthalide, a compound of formula (I) and picoxystrobin (ZA1963), a compound of formula (I) and polyoxin D, a compound of formula (I) and polyram, a compound of formula (I) and probenazole, a compound of formula (I) and prochloraz, a compound of formula (I) and procymidone, a compound of formula (I) and propamocarb, a compound of formula (I) and propiconazole, a compound of formula (I) and propineb, a compound of formula (I) and propionic acid, a compound of formula (I) and proquinazid, a compound of formula (I) and prothioconazole, a compound of formula (I) and pyraclostrobin, a compound of formula (I) and pyrazophos, a compound of formula (I) and pyribencarb, a compound of formula (I) and pyrifenox, a compound of formula (I) and pyrimethanil, a compound of formula (I) and pyroquilon, a compound of formula (I) and pyroxyfur, a compound of formula (I) and pyrrolnitrin, a compound of formula (I) and quaternary ammonium compounds, a compound of formula (I) and quinomethionate, a compound of formula (I) and quinoxyfen, a compound of formula (I) and quintozene, a compound of formula (I) and silthiofam, a compound of formula (I) and simeconazole, a compound of formula (I) and sipconazole (F-155), a compound of formula (I) and sodium pentachlorophenate, a compound of formula (I) and spiroxamine, a compound of formula (I) and streptomycin, a compound of formula (I) and sulphur, a compound of formula (I) and tebuconazole, a compound of formula (I) and tecloftalam, a compound of formula (I) and tecnazene, a compound of formula (I) and tetraconazole, a compound of formula (I) and thiabendazole, a compound of formula (I) and thifluzamid, a compound of formula (I) and 2-(thiocyanomethylthio)benzothiazole, a compound of formula (I) and thiophanate-methyl, a compound of formula (I) and thiram, a compound of formula (I) and tiadinil, a compound of formula (I) and timibenconazole, a compound of formula (I) and tolclofos-methyl, a compound of formula (I) and tolylfluanid, a compound of formula (I) and triadimefon, a compound of formula (I) and triadimenol, a compound of formula (I) and triazbutil, a compound of formula (I) and triazoxide, a compound of formula (I) and tricyclazole, a compound of formula (I) and tridemorph, a compound of formula (I) and trifloxystrobin (CGA279202), a compound of formula (I) and triforine, a compound of formula (I) and triflumizole, a compound of formula (I) and triticonazole, a compound of formula (I) and validamycin A, a compound of formula (I) and vapam, a compound of formula (I) and valiphenal a compound of formula (I) and vinclozolin, a compound of formula (I) and zineb, a compound of formula (I) and ziram, a compound of formula (I) and zoxamide, a compound of formula (I) and 3-[5-(4-chlorophenyl)-2,3-dimethylisoxazolidin-3-yl]pyridine, a compound of formula (I) and 5-chloro-7-(4-methylpiperidine-1-yl)-6-(2,4,6-trifluorophenyl)[1,2,4]triazolo[1,5-a]pyrimidine and a compound of formula (I) and N-(4-chloro-2-nitrophenyl)-N-ethyl-4-methyl-benzsulfonamide.

Compounds of formula (I) may be prepared using the methods below.

Compounds of formula (I) wherein R₄═H may be prepared by a [3+2]-cycloaddition of a carboximidoyl chloride (II) with an acetylenic carbinol (III):

The reaction may be carried out in the presence of an organic base such as triethylamine in an inert solvent such as DCE (1,2-dichloroethane), or an inorganic base such as sodium bicarbonate in a protic solvent such as isopropanol. Time and temperature of the reaction is not critical but may be at temperatures ranging from 20 to 60° C. for 1 to 24 h.

The carboximidoyl chlorides (II) may be prepared from the corresponding oximes using chlorinating reagents such as N-chlorosuccinimide or sodium hypochlorite (bleach), or may be obtained from commercial sources.

The acetylenic carbinols (III) may be obtained by addition of an organometallic acetylene (IV) (M=Li, MgX; X═Cl, Br) to an aldehyde R₂CHO (V), as shown below:

In certain cases, the [3+2]-cycloaddition proceeds more rapidly and in higher yield when the corresponding ketone (VI) of acetylenic carbinol (III) is used:

Compounds of formula (VII) are useful for making compounds of formula (I) as described below wherin the isoxazole (VII) is reduced (e.g. with sodium borohydride) to give (I).

In some cases, the regioisomer (VIII) is produced along with (I) in the [3+2]-cycloaddition. This regioisomer (VIII) generally is less active than (I) in bioevaluation.

Acetylenic ketone (VI) can be prepared from (III) by oxidation, for example with IBX (o-iodosobenzoic acid) in an inert solvent such as DMSO (dimethylsulfoxide) at any suitable time and temperature (e.g. 20° C. for 1 to 2 h). Reduction of isoxazole (VII) with sodium borohydride in an alcoholic solvent (e.g. ethanol) at 0° C. for 0.3 to 2 h produces the isoxazole (I) (R₄═H).

Isoxazoles in which R₄≠H may be prepared from (I) (R₄═H) using standard acylation or carbamoylation conditions. For example, the acetate derivative of (I) (R₄═COCH₃) is synthesized from the alcohol (I) (R═H) by reaction with acetic anhydride and pyridine in ether solvent at room temperature overnight. Acylations may be carried out using either acid anhydrides (e.g. acetic anhydride, propionic anhydride) or acid chlorides (e.g. benzoyl chloride) in the presence of an organic base in an inert solvent (e.g. ether, dichloromethane). Carbamoylations are effected by treating alcohols (I) with a strong base such as sodium hydride followed by a carbamoyl chloride (e.g. N,N-dimethylcarbamoyl chloride) in an inert solvent such as DMF (dimethylformamide).

Conventional techniques for the preparation or isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). Alternatively, the racemate (or a racemic precursor) may be reacted with a suitable optically active compound, for example, a carboxylic acid, or, in the case where the compound of formula (I) contains an acidic or basic moiety, a base or acid such as 1-phenylethylamine or tartaric acid. The resulting diastereomeric mixture may be separated by chromatography and/or fractional crystallization and one or both of the diastereoisomers converted to the corresponding pure enantiomer(s) by means well known to a skilled person. Conventional techniques known to those skilled in the art—are disclosed in, for example, Stereochemistry of Organic Compounds by E. L. Eliel and S. H. Wilen (Wiley, New York, 1994).

The invention is illustrated by the following Examples.

EXAMPLE 1 3-(2,6-Dichlorophenyl)-4-[(3-pyridyl)-hydroxymethyl]-5-trimethylsilyl-isoxazole (Table 1, compound 1) and 3-(2,6-dichlorophenyl)-5-[(3-pyridyl)-hydroxymethyl]-4-trimethylsilylisoxazole (Table 1, compound 2)

A mixture of 55 mg (0.24 mmol) of 2,6-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.24 mmol) of 1-(3-pyridyl)-3-trimethylsilyl-2-propyn-1-ol, and 20 mg (0.24 mmol) of sodium bicarbonate in 2 mL of isopropyl alcohol was heated at 55° C. for 24 h. The reaction mixture was diluted with ether. The ether layer was washed with saturated sodium chloride solution, and was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by preparative thin layer chromatography (prep TLC), and two products were isolated.

The less polar product (10 mg, 0.025 mmol) was identified as 3-(2,6-dichlorophenyl)-4-[(3-pyridyl)hydroxy-methyl]-5-trimethylsilylisoxazole. ¹H NMR (CDCl₃): δ 0.45 (br s, 9), 5.82 (s, 1), and 7.40 ppm (d, 1). MS m/z: 393.0 (M+H).

The more polar product was 3-(2,6-dichlorophenyl)-5-[(3-pyridyl)hydroxymethyl]-4-trimethylsilylisoxazole. ¹H NMR (CDCl₃): δ 0.20 (m, 9), 6.12 (s, 1), 7.80 (d, 1), and 7.87 ppm (d, 1). MS m/z: 393.0 (M+H).

EXAMPLE 2 5-(3-Chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole (Table 1, compound 4)

A mixture of 53 mg (0.24 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50mg (0.21 mmol) of 1-(3-pyridyI)-3-(3-chlorophenyl)-2-propyn-1-ol, and 26 mg (0.31 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. on a rotary table shaker equipped with a heated sand bath. After 20 h, an additional 20 mg of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride and 10 mg of sodium bicarbonate was added, and the reaction mixture was stirred and heated for another 16 h. The mixture was then diluted with ether, and the solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole.

¹H NMR (CDCl₃): δ 5.92 (br s, 1), 7.04 (d of d, 1), 7.12 (d, 1), 7.72 (m, 1), 8.86 (br s, 1), and 8.29 ppm (br s, 2). MS m/z: 430.9 (M+H).

EXAMPLE 3 5-(3-Chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)-acetoxymethyl]isoxazole

To a solution of 43 mg (0.10 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole in 2 mL of pyridine was added 19 μL (0.20 mmol) of acetic anhydride. The reaction was stirred overnight at room temperature, and then the pyridine was removed under vacuum. The residue was taken up in ethyl acetate, washed with saturated sodium chloride, and the ethyl acetate fraction dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by preparative thin layer chromatography (prep TLC) to give 35 mg (0.074 mmol) of 5-(3-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)acetoxymethyl]-isoxazole.

EXAMPLE 4 3-(2,4-Dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]isoxazole

To a solution of 200 mg (1.06 mmol) of 4,4-dimethyl-1-pyridyl-2-pentyn-1-ol in 2.5 mL of dimethyl sulfoxide (DMSO) was added 443 mg (1.58 mmol) of o-iodosobenzoic acid (IBX). The reaction mixture was stirred overnight at room temperature, and then the solid was removed by filtration. The filtrate was diluted with ether, and washed with saturated sodium chloride solution. The organic fraction was separated and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The ketonic product, 4,4-dimethyl-1-(3-pyridyl)-2-pentyn-1-one (182 mg) was used directly without any purification.

A mixture of 72 mg (0.32 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.32 mmol) of 4,4-dimethyl-1-(3-pyridyI)-2-pentyn-1-one, and 32 mg (0.38 mmol, 1.2 equivalents) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. for 16 h on a rotary table shaker. A second addition of 25 mg of carboximidoyl chloride and 10 mg of sodium bicarbonate was followed by another 20 h at 55° C. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 92 mg of oily product, 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]-isoxazole. ¹H NMR (CDCl₃): δ 1.47 (s, 9), 7.90 (m, 1), 7.60 (br s, 1) and 8.72 ppm (br s, 1). MS m/z: 375.0 (M+H).

EXAMPLE 5 3-(2,4-Dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridl)hydroxymethyl]-isoxazole (Table 1, compound 7)

To a solution of 92 mg (0.24 mmol) of 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)carbonyl]isoxazole in 5 mL of ethanol at 0° C. was added 20 mg (0.53 mmol) of sodium borohydride. After 2 h, the reaction mixture was poured into water, and the product was extracted several times with ethyl acetate. The combined ethyl acetate fractions were washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by prep TLC to yield 68 mg (0.18 mmol) 3-(2,4-dichlorophenyl)-5-(1,1-dimethylethyl)-4-[(3-pyridyl)hydroxy-methyl]isoxazole. ¹H NMR (CDCl₃): δ 1.52 (s, 9), 6.14 (br s, 1), 6.86 (d, 1), 7.38 (m, 1), 8.27 (br s, 1) and 8.33 ppm (m, 1). MS m/z: 377.0 (M+H).

EXAMPLE 6 5-(2-Chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole (Table 1, compound 14)

To a solution of 655 mg (4.8 mmol) of 2-chlorophenylacetylene in 10 mL of tetrahydrofuran (THF) cooled to −78° C. under a nitrogen atmosphere was added 3.0 mL (4.8 mmol) of 1.6M n-butyllithium in hexane. The solution was stirred at −78° C. for 2 h, and then a solution of 514 mg (4.8 mmol) of 3-pyridinecarboxaldehyde in 2.5 mL of tetrahydrofuran (THF) was added. After 3.5 h, the reaction mixture was poured into water. The organic product was extracted with ether several times. Combined ether extracts were washed with saturated sodium bicarbonate and dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation to give the oily 3-(2-chlorophenyI)-1-(3-pyridyl)-2-propyn-1-ol.

A mixture of 52 mg (0.23 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-ol, and 30 mg (0.36 mmol) of sodium bicarbonate in 3 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 15 mg (0.035 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. ¹H NMR (CDCl₃): δ 5.80 (br s, 1). MS m/z: 431.0 (M+H).

EXAMPLE 7 5-(2-Chlorophenyl)-3-(2,4-dichlorophenyl)-4-[3-pyridyl)hydroxymethyl]-isoxazole (Table 1, compound 14)

A mixture of 56 mg (0.25 mmol) of 2,4-dichloro-N-hydroxybenzenecarboximidoyl chloride, 60 mg (0.25 mmol) of 3-(2-chlorophenyl)-1-(3-pyridyl)-2-propyn-1-one, and 30 mg (0.36 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. An additional 30 mg of carboximidoyl chloride and 15 mg of sodium bicarbonate was then added, and the mixture was heated for another 20 h. The reaction mixture was cooled, diluted with ether, and then washed with saturated sodium bicarbonate. The ether fraction was dried over magnesium sulfate. The drying agent was filtered off, and the ether was removed by rotoevaporation. The crude product was purified by prep TLC to give 90 mg (0.21 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole.

¹H NMR (CDCl₃): δ 7.16 (m, 1), 7.60 (m,2), 7.92 (m, 1), 8.53 (br d, 1), and 8.74 ppm (br s, 1). MS m/z: 428.9 (M+H).

To a solution of 80 mg (0.19 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)carbonyl]isoxazole in 3 mL of ethanol at 0° C. was added 40 mg (1.06 mmol) of sodium borohydride. The mixture was stirred for 2 h and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was filtered off, and the ethyl acetate was removed by rotoevaporation. The crude product was purified by prep TLC to give 65 mg (0.15 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole.

¹H NMR (CDCl₃): δ 5.80 (br s, 1), 6.97 (m, 1), 8.23 (br s, 1), and 8.28 ppm (br s, 1). MS m/z: 431.0 (M+H).

EXAMPLE 8 5-(2-Chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[3-pyridyl)hydroxymethyl]-isoxazole (Table 1, Compound 15)

A solution of 59 mg (0.25 mmol) of 2,4-dichlorobenzylcarboximidoyl chloride (prepared according to G. Kumaran and G. H. Kulkarni, J. Org. Chem. 1997, 62, 1516), 50 mg (0.21 mmol) of 3-(2-chlorophenyI)-1-(3-pyridyl)-2-propyn-1-one, and 43 μL (0.31 mmol) of triethylamine in mL of dichloromethane was heated at 55° C. in a sealed vial overnight. The reaction mixture was cooled and diluted with ether, washed with saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The crude product was purified by prep TLC to give 50 mg (0.11 mmol) 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)carbonyl]isoxazole.

¹H NMR (CDCl₃): δ 4.23 (s, 2), 7.48 (d, 1), 7.88 (d of d, 1), 8.66 (br d, 1), 8.70 ppm (br s, 1). MS m/z: 442.9 (M+H).

To a solution of 50 mg (0.11 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)carbonyl]isoxazole in 15 mL of THF was added 21 mg (0.56 mmol) of sodium borohydride at room temperature. After 2 h, the solution was diluted with ethyl acetate, washed with saturated sodium chloride, and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The crude product was purified by prep TLC to give 39 mg (0.088 mmol) of 5-(2-chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole. ¹H NMR (CDCl₃): δ 3.91 (d, 1), 4.00 (d, 1), 6.97 (br s, 1), 7.64 (d, 1), 8.42 ppm (br m, 2). MS m/z: 445.0 (M+H).

EXAMPLE 9 5-(3-Chlorophenyl)-3-(2-fluoro-5-trifluoromethylphenyl)-4-[(3-pyridyl)-hydroxyl-methyl]isoxazole (Table 1, compound 29)

To a solution of 643 mg (3.10 mmol) of 2-fluoro-5-trifluoromethylbenzaldehyde oxime in 5 mL of dimethyl formamide (DMF) was added 456 mg (3.41 mmol) of N-chlorosuccinimide (see K.-C. Liu, B. R. Shelton, and R. K. Howe, J. Org. Chem. 1980, 45, 3916). The reaction mixture was stirred at room temperature overnight, and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation to give 675 mg (2.79 mmol) of pure white crystalline 2-fluoro-5-trifluoromethyl-N-hydroxybenzene-carboximidoyl chloride.

A mixture of 60 mg (0.25 mmol) of 2-fluoro-5-trifluoromethyl-N-hydroxybenzenecarboximidoyl chloride, 50 mg (0.21 mmol) of 3-(3-chlorophenyl) 1-(3-pyridyl)-2-propyn-1-one (prepared similarly to procedures noted above from lithio 3-chlorophenylacetylide and 3-pyridinecarboxaldehyde, followed by IBX oxidation), and 26 mg (0.36 mmol) of sodium bicarbonate in 2.5 mL of isopropyl alcohol was heated at 55° C. overnight with shaking. An additional 30 mg of carboximidoyl chloride and 15 mg of sodium bicarbonate were added, and the reaction was heated for another 24 h. The mixture was cooled and diluted with ether. The ether fraction was washed with saturated sodium chloride and dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The residue was purified by prepTLC to give 56 mg (0.13 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethylphenyl)-4-[(3-pyridyl)carbonyl]isoxazole. ¹H NMR (CDCl₃): δ 7.10 (t, 1), 7.41 (m, 1), 7.52 (m, 1), 8.65 (br s, 1), and 8.86 ppm (br s, 1). MS m/z: 447.0 (M+H).

To a solution of 56 mg (0.13 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethyl-phenyl)-4-[(3-pyridyl)carbonyl]isoxazole in 2 mL of ethanol was added 24 mg (0.63 mmol) of sodium borohydride. After 2 h at room temperature, the reaction mixture was diluted with ethyl acetate. The solution was washed with saturated sodium chloride and was dried over magnesium sulfate. The drying agent was filtered off, and solvent was removed by rotoevaporation. The residue was purified by prepTLC to give 44 mg (0.098 mmol) of 5-(3-chlorophenyl)-3-(2-fluoro-5-trifluoromethylphenyl)-4-[(3-pyridyl)hydroxymethyl]isoxazole.

¹H NMR (CDCl₃): δ 6.01 (s, 1), 7.01 (m, 1), 7.83 (m, 1), 8.27 (m, 1), and 8.35 ppm (br s, 1). MS m/z: 449.0 (M+H).

EXAMPLE 10 [3-(4-Chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyridin-3-yl-methanol (Table 1, compound 146) (i) Preparation of 3-(2,4-difluorophenyl)-1-pyridin-3-yl-propynone (3)

1-Ethynyl-2,4-difluorobenzene (24 g, 0.17 mol) was dissolved in THF (350 ml) and the reaction mixture was cooled at −78° C. A solution of n-BuLi, 2.5 M in hexane, (76.5 ml, 0.19 mol) was added dropwise over 70 minutes maintaining the temperature below −70° C. The mixture was stirred at this temperature for a further 10 minutes after the addition was finished. A solution of the Weinreb amide 2 (prepared according to WO 05/097760, Letters in Organic Chemistry, 4, 20, 2007) (28.9 g, 0.17 mol) in THF (100 ml) was added dropwise over 20 minutes to the solution above keeping the temperature below −70° C. The mixture was now warmed to −50° C. obtaining a solution that was further stirred for 1 hour at this temperature. The reaction mixture was quenched with a saturated solution of ammonium chloride (100 ml) and allowed to warm to room temperature. The reaction was then poured into a mixture of ethyl acetate/water. Successively, the aqueous phase was washed twice with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulphate, filtered and concentrated. The crude was recrystallised from diethyl ether obtaining 28 g of the desired product. The mother liquors were concentrated and the residue was purified by column chromatography on alumina using a mixture of cyclohexane/ethyl acetate 3:1. Totally, 29.8 g (70%) of brown compound were obtained.

¹H NMR (CDCl₃): δ 7.02 (m, 1), 7.58 (m, 1), 7.71 (m, 1), 8.56 (m, 1) 8.90 (m, 1) and 9.48 ppm (m, 1). MS m/z: 244.0 (M+H).

(ii) Preparation of [3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyridin-3-yl-methanone (5)

A mixture of 46.7 g (0.22 mol) of 2-fluoro-4-chloro-N-hydroxybenzenecarboximidoyl chloride (prepared by analogy to the method of preparation of 2-fluoro-5-trifluoromethyl-N-hydroxybenzene-carboximidoyl chloride Example 9), 42 g (0.17 mol) of 3-(2,4-difluorophenyl)-1-pyridin-3-yl-propynone (3), and 21.76 g (0.26 mol) of sodium bicarbonate in 500 mL of isopropyl alcohol was heated at 85° C. for 21 hours. The reaction mixture was diluted with ethyl acetate and washed successively with saturated ammonium chloride, water, and saturate sodium chloride solution, and was dried over magnesium sulfate. The drying agent was filtered off and the ethyl acetate was removed by rotoevaporation. The crude was recrystallised from diethyl ether obtaining the desired product as a yellowish solid (50.28 g, 70.2%). ¹H NMR (CDCl₃): δ 6.75 (m, 1), 7.05 (m, 2), 7.27 (m, 2), 7.67 (t, 1), 7.80 (m, 1), 8.03 (m, 1), 8.66 (m, 1) and 8.82 ppm (d, 1). MS m/z: 415 (M+H).

(iii) Preparation of [3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyridin-3-yl-methanol (6)

To a solution of 5 (26.5 g, 63.9 mmol) in a mixture of THF/methanol (400 ml/40 ml) at 0° C. was added 2.42 g (63.7 mmol) of sodium borohydride. The mixture was stirred for 1.5 hours and then diluted with ethyl acetate. The ethyl acetate solution was washed with saturated sodium chloride solution and dried over magnesium sulfate. The drying agent was filtered off and the ethyl acetate was removed by rotoevaporation. The reaction mixture was purified by column chromatography using a mixture of heptane/ethyl acetate 1:1. The desired compound was obtained as white crystals (17.5 g, 66%). mp=138-140° C.

¹H NMR (CDCl₃): δ 4.19 (bs, 1), 5.89 (s, 1), 6.99 (m, 5), 7.28 (t, 1), 7.43 (d, 1), 7.59 (q, 1), and 8.19 (d, 1) and 8.23 ppm (d, 1). MS m/z: 417 (M+H).

EXAMPLE 11 (R)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyridin-3-yl-methanol (Table 1, compound 153: (R)-146))

Each enantiomer was isolated by preparative chromatography using the racemic mixture 6 as starting material.

Preparative Method:

Column: 250×76 mm CHIRALPAK® AD 20 μm;

Mobil phase: n-heptane/ethanol 70/30 (v/v)

Flow rate: 270 ml/min

Detection: UV 280 nm

Temperature: 25° C.

Analytical Method:

Column: 250×4.6 mm CHIRALPAK® AD-H 5 μm;

Mobil phase: n-heptane/ethanol/diethylamine 70/30/0.1 (v/v/v)

Flow rate: 1 ml/min

Detection: UV 230 nm

Temperature: 25° C.

The first eluting enantiomer had a retention time of 7.6 min ([α]=+58.07, C=0.025 M, THF) while the second enantiomer had a retention time of 9.9 min ([α]=−57.59, C=0.025 M, THF). The first eluting enantiomer is the (R)-enantiomer. The second eluting enantiomer is the (S)-enantiomer. The (R)-enantiomer was found to possess the majority of PGR activity.

The compounds of formula (I) in Table 1 may be prepared by analogous methods.

TABLE 1 Compound No. Structure Chemical Name 1

3-(2,6-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-trimethylsilylisoxazole 3

3-(2,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-trimethylsilylisoxazole 4

5-(3-Chlorophenyl)-3-(2,4-dichlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 6

3-(2,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-phenylisoxazole 7

3-(2,4-Dichlorophenyl)-5-(1,1-dimethylethyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 12

3-(2,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2-thienyl)isoxazole 13

3-(2,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 14

5-(2-Chlorophenyl)-3-(2,4-dichlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 15

5-(2-Chlorophenyl)-3-(2,4-dichlorobenzyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 16

3-(4-Chlorophenyl)-5-(1,1-dimethylethyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 17

3-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2- trifluoromethylphenyl)-isoxazole 18

4-[(3-Pyridyl)hydroxymethyl]-3-(4- trifluoromethoxyphenyl)-5-(2- trifluoromethylphenyl)-isoxazole 19

4-[(3-Pyridyl)hydroxymethyl]-3-(3- trifluoromethylphenyl)-5-(2- trifluoromethylphenyl)-isoxazole 20

3-(3,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2- trifluoromethylphenyl)-isoxazole 21

3-(2,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2- trifluoromethylphenyl)-isoxazole 22

3-(4-Chlorophenyl)-5-(4-methylphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 23

5-(4-Methylphenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(4- trifluoromethoxyphenyl)-isoxazole 24

5-(4-Methylphenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(3- trifluoromethylphenyl)-isoxazole 25

3-(3,4-Dichlorophenyl)-5-(4-methylphenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 26

3-(2,4-Dichlorophenyl)-5-(4-methylphenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 27

3-(2,4-Dichlorophenyl)-5-phenoxymethyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 28

3-(2,4-Dichlorophenyl)-4-phenoxymethyl-5-[(3- pyridyl)hydroxymethyl]-isoxazole 29

5-(3-Chlorophenyl)-3-(2-fluoro-5- trifluoromethylphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 30

5-(3-Chlorophenyl)-3-(4-cyanophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 31

5-(2-Chlorophenyl)-3-(4-cyanophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 32

5-(4-Chlorophenyl)-3-(2,4-dichlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 33

3-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3- trifluoromethylphenyl)-isoxazole 34

4-[(3-Pyridyl)hydroxymethyl]-3-(4- trifluoromethoxyphenyl)-5-(3- trifluoromethylphenyl)-isoxazole 35

4-[(3-Pyridyl)hydroxymethyl]-3-(3- trifluoromethylphenyl)-5-(3- trifluoromethylphenyl)-isoxazole 36

3-(3,4-Dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3- trifluoromethylphenyl)-isoxazole 37

3-(4-Chlorophenyl)-5-phenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 38

5-Phenyl-4-[(3-pyridyl)hydroxymethyl]-3-(4- trifluoromethoxyphenyl)-isoxazole 39

5-Phenyl-4-[(3-pyridyl)hydroxymethyl]-3-(4- trifluoromethylphenyl)-isoxazole 40

3-(2,4-Dichlorophenyl)-5-phenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 41

3-(3,4-Dichlorophenyl)-5-phenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 42

5-(3-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(4- trifluoromethoxyphenyl)-isoxazole 43

5-(3-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(3- trifluoromethylphenyl)-isoxazole 44

5-Benzyl-3-(2,4-dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 45

5-Benzyl-3-(3,4-dichlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 46

5-Benzyl-4-[(3-pyridyl)hydroxymethyl]-3-(4- trifluoromethoxyphenyl)-isoxazole 47

5-Benzyl-4-[(3-pyridyl)hydroxymethyl]-3-(3- trifluoromethylphenyl)-isoxazole 48

3-(4-Chlorophenyl)-5-phenoxymethyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 49

3-(3,4-Dichlorophenyl)-5-phenoxymethyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 50

5-Phenoxymethyl-4-[(3-pyridyl)hydroxymethyl]- 3-(4-trifluoromethoxyphenyl)-isoxazole 51

5-Phenoxymethyl-4-[(3-pyridyl)hydroxymethyl]- 3-(3-trifluoromethylphenyl)-isoxazole 52

5-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(2-thienyl)isoxazole 53

5-(4-Chlorophenyl)-3-isopropyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 54

5-(4-Chlorophenyl)-3-pentyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 55

5-(4-Chlorophenyl)-3-(2-fluoro-4- trifluoromethylphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 56

3-(2-Fluoro-4-trifluoromethylphenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 57

3-Isopropyl-4-[(3-pyridyl)hydroxymethyl]-5-(3- thienyl)isoxazole 58

3-Pentyl-4-[(3-pyridyl)hydroxymethyl]-5-(3- thienyl)isoxazole 59

4-[(3-Pyridyl)hydroxymethyl]-3-(2-thienyl)-5-(3- thienyl)-isoxazole 60

3-(3,4-Methylenedioxybenzyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 61

5-(4-Chlorophenyl)-3-(3,4- methylenedioxybenzyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 62

5-(3-Chlorophenyl)-3-phenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 63

5-(4-Methylphenyl)-3-phenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 64

5-(Phenoxymethyl)-3-phenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 65

5-(4-Methylphenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(3-thienyl)isoxazole 66

5-(3-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(3-thienyl)isoxazole 67

5-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(3-thienyl)isoxazole 68

5-(3-Chlorophenyl)-3-(3,4- difluoromethylenedioxyphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 69

3-(3,4-Difluoromethylenedioxy-phenyl)-5-(4- methylphenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 70

3-(4-Chlorophenyl)-5-(3-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 71

3-(2-Fluoro-5-trifluoromethylphenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 72

5-(4-Chlorophenyl)-3-(2-fluoro-5- trifluoromethylphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 73

3-(4-Chlorophenyl)-5-phenyl-4-[(2- pyridyl)hydroxymethyl]-isoxazole 74

3-(2,4-Dichlorobenzyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2-thienyl)isoxazole 75

5-(3-Chloro-4-methylphenyl)-3-(4- chlorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 76

5-(3-Chloro-4-fluorophenyl)-3-(4-chlorophenyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 77

3-(4-Chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 78

3-(4-Chlorophenyl)-5-(2-methoxyphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 79

5-(3-Chlorophenyl)-3-(4-methylphenyl-4-[(3- pyridyl)hydroxymethyl]-isoxazole 80

3-(4-tert-Butylphenyl)-5-(3-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 81

5-(3-Chlorophenyl)-3-(4-isopropoxyphenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 82

5-(3-Chlorophenyl)-3-(4-butoxyoxyphenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 83

5-(3-Chlorophenyl)-3-(4-phenoxyphenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 84

3-(4-Chlorophenyl)-5-(5-methyl-3-thienyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 85

3-(4-Chlorobenzyl)-5(-3-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 86

3-(2,4-Dichlorophenyl)-5-(4-fluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 87

3-(2-Chlorophenyl)-5-(4-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 88

3-(4-Chlorophenyl)-5-(4-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 89

5-(4-Chlorophenyl)-3-(4-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 90

5-(2-Chlorophenyl)-3-(4-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 91

3-(4-Chlorophenyl)-5-(4-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 92

3-(4-Chlorophenyl)-5-(2-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 93

3-(4-Fluorophenyl)-5-(4-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 94

3-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 95

5-(1-Chloro-1-methylethyl)-3-(4- chlorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 96

5-(4-Chlorophenyl)-3-(5-chloro-2-thienyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 97

5-(3-Chlorophenyl)-3-(5-chloro-2-thienyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 98

3-(5-Chloro-2-thienyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 99

5-(4-Chlorophenyl)-3-(5-chloro-3-thienyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 100

5-(3-Chlorophenyl)-3-(5-chloro-3-thienyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 101

3-(5-Chloro-3-benzo[b]thienyl)-5-(3- chlorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 102

5-(3-Chlorophenyl)-3-(2,5-dichloro-3-thienyl) 4-[(3-pyridyl)hydroxymethyl]-isoxazole 103

3-(5-Chloro-3-benzo[b]thienyl)-5-(4- chlorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 104

5-(4-Chlorophenyl)-3-(2,5-dichloro-3-thienyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 105

3-(4-Chlorophenyl)-5-(3,5-difluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 106

3-(5-Chloro-2-thienyl)-5-(3,5-difluorophenyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 107

3-(4-Chlorophenyl)-5-(3-chlorophenyl)-4-[(5- pyrimidinyl)hydroxymethyl]-isoxazole 108

5-(3-Chlorophenyl)-3-(5-chloro-2-thienyl)-4- [(5-pyrimidinyl)hydroxymethyl]-isoxazole 109

3-(5-Bromo-2-thienyl)-5-(4-chlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 110

3-(5-Bromo-2-thienyl)-5-(3-chlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 111

3-(2-Chlorophenyl)-5-(4-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 112

3-(2-Chlorophenyl)-5-(3-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 113

3-(3-Chlorophenyl)-5-(4-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 114

3-(3-Chlorophenyl)-5-(3-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 115

5-(4-Butylphenyl)-3-(4-chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 116

3-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2-thienyl)isoxazole 117

5-(3-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(4- trifluorophenyl)isoxazole 118

5-(4-Chlorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(4- trifluorophenyl)isoxazole 119

5-(3-Chlorophenyl)-3-(2,4-dichlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 120

5-(3-Chlorophenyl)-3-(2,4-difluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 121

5-(4-Chlorophenyl)-3-(2,4-difluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 122

3-(4-Chlorophenyl)-5-(5-chloro-2-thienyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 123

3-(5-Chloro-2-thienyl)-5-(5-chloro-2-thienyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 124

5-(4-Chlorophenyl)-3-(3,5-difluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 125

3-(4-Chlorophenyl)-5-[1-methyl-1-(4- chlorophenoxy)ethyl]-4-[(3- pyridyl)hydroxymethyl]-isoxazole 126

3-(4-Chlorophenyl)-5-(5-methyl-2-thienyl)-4- (3-pyridyl)hydroxymethyl]-isoxazole 127

5-[(3-Chlorophenoxy)methyl]-3-(4- chlorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 128

5-[(4-Chlorophenoxy)methyl]-3-(4- chlorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 129

3-(2,4-Difluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2-thienyl)isoxazole 130

5-(5-Chloro-2-thienyl)-3-(2,4-difluorophenyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 131

3-(2,4-Difluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 132

3-(2,4-Difluorophenyl)-5-(4-fluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 133

3-(4-Chlorophenyl)-5-(2,4-difluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 134

3-(5-Chloro-2-thienyl)-5-(2,4-difluorophenyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 135

5-(2,4-Difluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-3-(3-thienyl)isoxazole 136

5-(5-Bromo-2-thienyl)-3-(2,4-difluorophenyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 137

5-(5-Bromo-2-thienyl)-3-(4-chlorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 138

5-(4-Chlorophenyl)-3-(2-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 139

5-(3,5-Diflorophenyl)-3-(2-fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-isoxazole 140

5-(5-Chloro-2-thienyl)-3-(2-fluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 141

5-(5-Bromo-2-thienyl)-3-(2-fluorophenyl)-4- [(3-pyridyl)hydroxymethyl]-isoxazole 142

3-(2-Fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(2-thienyl)isoxazole 143

3-(2-Fluorophenyl)-4-[(3- pyridyl)hydroxymethyl]-5-(3-thienyl)isoxazole 144

3-(2-Fluoro-4-Chlorophenyl)-5-(2,4- difluorophenyl)-4-[(3- pyrimidyl)hydroxymethyl]-isoxazole 145

3-(4-Chlorophenyl)-5-(2,4-difluorophenyl)-4- [(3-pyrimidyl)hydroxymethyl]-isoxazole 146

3-(2-Fluoro-4-Chlorophenyl)-5-(2,4- difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole 147

3-(2,4-Chlorophenyl)-5-(2-Chlorophenyl)-4- [(3-pyrimidyl)hydroxymethyl]-isoxazole 148

3-(2-Fluoro-4-Chlorophenyl)-5-(2- Chlorophenyl)-4-[(3- pyrimidyl)hydroxymethyl]-isoxazole 149

3-(4-Chlorophenyl)-5-(2-Methoxypyridine)-4- [(3-pyrimidyl)hydroxymethyl]-isoxazole 150

3-(4-Chlorophenyl)-5-(4-Fluorophenyl)-4-[(3- pyrimidyl)hydroxymethyl]-isoxazole 151

3-(4-Chlorophenyl)-5-(2,4-Fluorophenyl)-4- [(3-pyrimidyl)hydroxymethyl]-isoxazole 152

3-(2,4-Diluoro)-5-(2-Chloro-4-Fluorophenyl)- 4-[(3-pyridyl)hydroxymethyl]-isoxazole 153

(R)-3-(2-Fluoro-4-Chlorophenyl)-5-(2,4- difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]- isoxazole

TABLE 2 [MH+] Compound (retention time) Structure 154 [400/402](1.42)

155 [369/371](3.16)

156 [355/357](1.61)

157 [408/410](1.56)

158 [413/415](1.76)

159 [416/418](1.59)

160 [377/379](1.45)

161 [357/359](4.09)

162 [443/445](3.52)

163 [443/445](3.56)

164 [352](1.38)

165 [424/426](1.60)

166 [409/411](1.21)

167 [407/409](1.63)

168 [489/491](1.74)

169 [317/319](1.15)

170 [447/449](1.81)

171 [411/413](1.48)

172 [412/414](1.79)

173 [452/454](1.92)

174 [448/450](1.86)

175 [464/466](1.92)

176 [485/487](1.97)

177 [451](1.65)

178 [501](1.76)

179 [469](1.83)

180 [331/333](3.13, 3.18)

181 [459/461](1.97)

182 [467/469](1.86)

183 [405/407](1.63)

184 [394/396](0.90)

185 [353/355](0.84)

186 [422/424](1.25)

187 [351/353](1.42)

188 [467/469](1.73)

189

3-(2-Fluoro-4-Chlorophenyl)- 5-(Cyclohexyl)-4[(3- pyridyl)hydroxymethyl]- isoxazole 190

3-(2-Fluoro-4-Chlorophenyl)- 5-(1,1-dimethylethyl)-4-[(3- pyrimidyl)hydroxymethyl]- isoxazole 191

3-(1,1-dimethyl-butyl)-5-(2- Fluoro-4-Chlorophenyl)-4[(3- pyridyl)hydroxymethyl]- isoxazole 192

3-(2-methyl-butyl)-5-(2- Fluoro-4-Chlorophenyl)-4[(3- pyridyl)hydroxymethyl]- isoxazole 193

3-(2-Fluoro-4-Chlorophenyl)- 5-(1-methoxy-propyl)-4[(3- pyridyl)hydroxymethyl]- isoxazole 194

3-(2-Fluoro-4-Chlorophenyl)- 5-(1-methoxy-cyclohexyl)- 4[(3-pyridyl)hydroxymethyl]- isoxazole 195

3-(2-Fluoro-4-Chlorophenyl)- 5-(1-methoxy-1-methyl- ethyl)-4[(3- pyridyl)hydroxymethyl]- isoxazole

EXAMPLE B1 Biological Evaluation of Plant Growth Effects on Cereals

Plants of winter wheat and summer wheat were sprayed at the beginning of stem elongation, three weeks after sowing. Formulated test compounds 144, 145 and 146 were sprayed at 225 g a.i. (active ingredient)/ha, each, top over leaf with a boom sprayer on the plants. After the spray the plants were transferred to a greenhouse and 28 days after the spray the plant growth reduction was visually evaluated versus an untreated control. Results are summarized in Table 2.

TABLE 2 Percentage of plant growth reduction after spray of summer and winter wheat with 225 ga.i./ha of 3 different test compounds Winter Wheat Summer Wheat Compound % reduction % reduction 144 7.5 10 145 5 17.5 146 10 10

EXAMPLE B2 Biological Evaluation of Plant Growth Regulation Effects on Grape

Five weeks old grape seedlings cultivar (cv.) Gutedel were treated with the formulated test compound in a spray chamber. After an incubation period of 8 days at 22° C. and 80% relative humidity (r.h.) in a greenhouse, the plant growth regulating effects were assessed.

Compounds 144, 145, 147, 148, 149, 150, 151, 152 and 153 showed plant height decreased at 200 ppm

EXAMPLE B3 Biological Evaluation of Plant Growth Regulation Effects on Wheat

Two weeks old wheat plants cultivar (cv.). Riband were treated with the formulated test compound in a spray chamber. After an incubation period of 8 days at 22° C. and 80% relative humidity (r.h.) in a greenhouse, the plant growth regulating effects were assessed.

Compound 144 showed plant height decreased at 200 ppm.

Fungicidal Compounds

It has surprisingly been found that the isoxazole compounds of formula (II), derived from compound 146, exhibit unexpected fungicidal activity and are therefore suitable for use in agriculture as crop protection agents to combat or prevent fungal infestations, or to control other pests such as weeds, insects, or acarids that are harmful to crops.

Accordingly, in an additional aspect, the present invention provides a compound of formula (II)

wherein R⁴ is H or acyl, preferably H;

or an agrochemically acceptable salt thereof.

In a preferred embodiment, the present invention provides the compound formula (S)-(II)

wherein R⁴ is H or acyl;

or an agrochemically acceptable salt thereof.

Most preferably, the present invention provides the compound (S)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyridin-3-yl-methanol (compound (S)-(146)).

Preferably, the compounds of formula (S)-(II), and preferably (S)-(146), are provided as single enantiomers having an enantiomeric excess (e.e.) of at least 40%, for example, at least 50%, 60%, 70% or 80%, preferably at least 90%, more preferably at least 95%, yet more preferably at least 98% and most preferably at least 99%.

Accordingly there is provided a composition comprising a compound of formula (S)-(II), and preferably (S)-(146), and an agriculturally acceptable diluent or carrier. The compound of formula (S)-(II), and preferably (S)-(146), and compositions thereof are suitable for controlling and preventing plant pathogenic microorganisms, especially fungal organisms, including those disclosd in International Patent Application WO 2006/031631.

In particular, the present invention provides a method for controlling or preventing infestation of cultivated plants by pathogenic microorganisms, comprising applying a compound of formula (S)-(II), and preferably (S)-(146), to said plants, parts thereof or the locus thereof in an amount effective to control said microorganisms. Preferably, the organism is a fungal organism and more preferably, said fungal organism is selected from the group consisting of Septoria tritici, Stagonospora nodorum, Phytophthora infestans, Botrytis cinerea, Sclerotinia homoeocarpa and Puccinia recondite.

The present invention also encompasses compositions, combinations and plants as described herein and in International Patent Application WO 2006/031631.

Biological examples: This fungicidal properties of compound (S)-(146) were demonstrated in the following examples.

Botrytis cinerea (Gray mould): Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically after 72 hours. Compound (S)-(146) gave at least 80% control of Botrytis cinerea at 200 ppm.

Mycosphaerella arachidis (syn. Cercospora arachidicola), Brown leaf spot of groundnut (peanut): Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically after 72 hours at 620 nm. Compound (S)-(146) gave at least 80% control of Mycosphaerella arachidis at 200 ppm.

Septoria tritici (leaf blotch): Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically after 72 hours. Compound (S)-(146) gave at least 80% control of Septoria tritici at 200 ppm.

Monographella nivalis (syn. Microdochium nivale, Fusarium nivale), snow mould, foot rot of cereals: Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically after 72 hours at 620 nm. Compound (S)-(146) gave at least 80% control of Monographella nivalis at 200 ppm.

Fusarium culmorum (root rot): Conidia of the fungus from cryogenic storage were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal spores was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically after 48 hours. Compound (S)-(146) gave at least 80% control of Fusarium culmorum at 200 ppm.

Rhizoctonia solani (foot rot, damping-off): Mycelial fragments of the fungus, prepared from a fresh liquid culture, were directly mixed into nutrient broth (PDB potato dextrose broth). After placing a (DMSO) solution of the test compounds into a microtiter plate (96-well format) the nutrient broth containing the fungal mycelium was added. The test plates were incubated at 24° C. and the inhibition of growth was determined photometrically after 48 h. Compound (S)-(146) gave at least 80% control of Rhizoctonia solani at 200 ppm. 

1. (deleted)
 2. (deleted)
 3. (deleted)
 4. (deleted)
 5. (deleted)
 6. (deleted)
 7. (deleted)
 8. (deleted)
 9. (deleted)
 10. (deleted)
 11. (deleted)
 12. (deleted)
 13. (deleted)
 14. A compound selected from: 3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole; 3-(2,4-chlorophenyl)-5-(2-chlorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(2-fluoro-4-chlorophenyl)-5-(2-chlorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(4-chlorophenyl)-5-(2-methoxypyridine)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(4-chlorophenyl)-5-(4-fluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(4-chlorophenyl)-5-(2,4-fluorophenyl)-4-[(3-pyrimidyl)hydroxymethyl]-isoxazole; 3-(2,4-difluorophenyl)-5-(2-chloro-4-fluorophenyl)-4-[(3pyridyl)hydroxymethyl]-isoxazole; and (R)-3-(2-fluoro-4-chlorophenyl)-5-(2,4-difluorophenyl)-4-[(3-pyridyl)hydroxymethyl]-isoxazole; and salts thereof.
 15. (deleted)
 16. A method of regulating plant growth of crops of useful plants, which comprises applying to said plants, to one or more parts of said plants, or to the locus thereof or plant propagation material, a compound having the formula (I)

wherein R₁ is alkyl optionally substituted with hydroxy, phenyl or halophenyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, phenoxy, alkoxyalkynyl, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; R₂ is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; R₃ is H; alkyl; alkoxy; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkynyl, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or alkylsilyl; and R₄ is H or acyl; or a salt thereof; as a plant growth regulator.
 17. A method according to claim 16, which comprises one or more applications of one of more compounds of formula (I) alone or in conjunction with one or more customary plant protection formulating auxiliaries.
 18. A method according to claim 17 wherein two or more applications are carried out in sequence, and wherein the two or more applications have the same or different concentration or combinations of compounds of formula (I) or both.
 19. A method according to claim 16 wherein the useful crop plants are selected from the group consting of cereals, rice, beets, leguminous plants, oil plants, cucumber plants, fibre plants, vegetables, plantation crops, ornamentals, vines, bushberries, caneberries, cranberries, peppermint, rhubarb, spearmint, sugar cane and turf grasses.
 20. A method according to claim 16 wherein the plant growth regulating effect is an inhibition or a retardation of the plant growth.
 21. An agricultural composition comprising one or more compounds of formula (I) and one or more customary plant protection auxiliaries wherein said compound of formula (I) has the formula

wherein R₁ is alkyl optionally substituted with hydroxy, phenyl or halophenyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, phenoxy, alkoxyalkynyl, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; R₂ is alkyl; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; R₃ is H; alkyl; alkoxy; alkoxyalkyl; haloalkyl; arylalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryloxyalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; arylthioalkyl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; aryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, alkoxyalkynyl, cyano, nitro; heteroaryl optionally substituted with halogen, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, alkylthio, haloalkoxy, cyano, or nitro; or alkylsilyl; and R₄ is H or acyl; or a salt thereof; as a plant growth regulator.
 22. A compound of the formula (S)-(II)

wherein R⁴ is H or acyl; or an agrochemically acceptable salt thereof.
 23. A compound according to claim 22 which is (S)-[3-(4-chloro-2-fluorophenyl)-5-(2,4-difluorophenyl)isoxazol-4-yl]pyridin-3-yl-methanol


24. A composition comprising a compound according to claim 22, or an agrochemically acceptable salt thereof, and an agrochemically acceptable diluent or carrier.
 25. (deleted)
 26. A compound or agrochemically acceptable salt thereof wherein said compound has the formula:

wherein R⁴ is H or acyl. 